Leukemia is the name applied to a group of related cancers which arise from the bone marrow and other blood-producing organs.
The cancerous cells reproduce rapidly, suppressing the production of 1) normal white cells that are essential to fighting infection in the body, 2) red cells needed to carry oxygen in the blood, and 3) platelets needed in the coagulation of blood. The uncontrolled proliferation of the stem cells in the bone marrow affects the production of the essential mature cells. Cancer cells may spread to the liver, spleen, lymph nodes, genitals or the brain (Tran, 1995).
Two forms of leukemia exist, the acute form which is of sudden onset and rapid progression, commonly found in children, and the chronic form, which progresses slowly with few symptoms for many years (even up to 20 years). A large proportion of acute or childhood leukemia (50-70%) is now curable since the advance of therapeutic strategies involving chemoactive drugs, radiation and bone marrow transfusion techniques (Tran, 1995).
Chronic leukemia is a disease of too many mature white cells (Cherath, 1995). Unlike acute leukemia, in which the process of maturation of the stem cell precursors is interrupted, in chronic leukemia the cells are still able to mature but, although appearing normal, they do not function as mature cells, but multiply slowly and in an unregulated way. They survive much longer than normal white cells and build up in the body. Two types of chronic leukemia exist. Chronic lymphocytic leukemia (CLL) involves the B and T lymphocytes, with abnormalities of the former being more common. In chronic myelogenous leukemia (CML), the cells affected are the granulocytes.
CML is a serious disease, still with a poor prognosis. Some 32% of newly diagnosed patients will survive 5 years (Cherath, 1995). The drug STI-571 (known also as Gleevac and Imatinib)(Mauro et al., 2002; Seppa, 2001; Lim and Muir, 2001; Rajaratnam and Edwards, 2001; O'Brien, 2001) created considerable hope for patients with advanced CML, as it appeared to reduce significantly elevated white cell counts. Unfortunately, leukemia cells develop resistance to the drug as treatment continues and the disease recurs. There therefore remains a need for improved treatments for CML.
The hepoxilins are biologically active metabolites of arachidonic acid formed through the 12(S)-lipoxygenase pathway. Four natural hepoxilins have been identified, the A-type hepoxilins consisting of two epimers having a hydroxyl group at carbon 8 (8(S, R)-hydroxy-11(S), 12(S)-epoxy-eicosa-5Z, 9E, 14Z-trienoic acid) and the B-type, two epimers having a hydroxyl group at carbon 10 (10(S,R)-hydroxy-11(S), 12(S)-epoxy-eicosa-5Z, 8Z, 14Z-trienoic acid).
A number of hepoxilin analogs have been described which, along with the native hepoxilins, exhibit a variety of pharmacological effects, including raising intracellular calcium, inhibiting thromboxane formation and action (International Patent Application WO 02/38157), stimulation of insulin release (International Patent Application WO 01/10422) and lowering of blood glucose.
It has not, however, previously been shown or suspected that hepoxilin analogs would be effective to control the growth of cancerous cells.